Objectives: To explore the relationship between HAND2 gene and protein expression and the development of endometrial carcinoma (EC). Materials and Methods: The expression of HAND2 protein was detected by immunohistochemistry in 77 cases of EC paraffin block and their matched adjacent tissues. Western blot, real-time polymerase chain reaction (RT-PCR) were used to detect the expression of HAND2 protein and mRNA HAND2 expression in 34 cases of EC fresh tissue and paired adjacent tissues. Results: The expression of HAND2 protein and the content of HAND2 mRNA in EC tissue were significantly lower than those in the non-tumorous tissue adjacent to EC. The positive expression rates of HAND2 protein in type I and type II EC were 19.67% and 50.00%, respectively. The expression of HAND2 protein in G1, G3, and G2 EC were 30.43%, 26.32%, 18.75%, respectively, with no statistically difference. The positive expression rates of HAND2 in the two groups of specimens with shallow and deep muscularis infiltrating were 40.63% and 15.56%, respectively. With the increase of EC FIGO stage, the positive expression rates of HAND2 protein decreased, and the difference was statistically significant (p < 0.05). Conclusions: HAND2 mRNA and protein low expressed in EC tissues, which suggested the degree of endometrial malignancy. HAND2 may be helpful to the early diagnosis, treatment, and to evaluate the prognosis of endometrial cancer.